Ferrara et al. Pediatric Rheumatology (2018) 16:46
https://doi.org/10.1186/s12969-018-0255-8
REVIEW Open Access
Methotrexate in juvenile idiopathic arthritis:
advice and recommendations from the
MARAJIA expert consensus meeting
Giovanna Ferrara1†, Greta Mastrangelo2†, Patrizia Barone3, Francesco La Torre4, Silvana Martino5,
Giovanni Pappagallo6, Angelo Ravelli7, Andrea Taddio8, Francesco Zulian9, Rolando Cimaz2* On behalf of the
Rheumatology Italian Study Group
Abstract
Background: Conventional pharmacological therapies for the treatment of juvenile idiopathic arthritis (JIA) consist
of non-biological, disease-modifying antirheumatic drugs, among which methotrexate (MTX) is the most commonly
prescribed. However, there is a lack of consensus-based clinical and therapeutic recommendations for the use of
MTX in the management of patients with JIA. Therefore, the Methotrexate Advice and RecommendAtions on
Juvenile Idiopathic Arthritis (MARAJIA) Expert Meeting was convened to develop evidence-based recommendations
for the use of MTX in the treatment of JIA.
Methods: The preliminary executive committee identified a total of 9 key clinical issues according to the population,
intervention, comparator, outcome (PICO) approach, and performed an evidence-based, systematic, literature review.
During the subsequent Expert Meeting, the relevant evidence was assessed and graded, and 10 recommendations
were made.
Results: Recommendations relating to the efficacy, optimal dosing and route of administration and duration of
treatment with MTX in JIA, and to the issue of folic acid supplementation to prevent MTX side effects, use of MTX in
the treatment of chronic JIA-associated uveitis, combination treatment with biologic agents, and the use of vaccinations
in patients with JIA were developed. The selected topics were considered to represent clinically important issues facing
clinicians caring for patients with JIA. Evidence was insufficient to formulate recommendations for the use of biomarkers
predictive of treatment response.
Conclusions: These consensus recommendations provide balanced and evidence-based recommendations designed to
have broad value for physicians and healthcare clinicians involved in the clinical management of patients with JIA.
Keywords: Juvenile idiopathic arthritis, Methotrexate, Consensus
Background criteria of the International League of Associations for
Juvenile idiopathic arthritis (JIA) is one of the most Rheumatology (ILAR), the term JIA covers seven mutually
common chronic conditions of childhood. JIA comprises exclusive categories with differences in their clinical pres-
a group of heterogeneous forms of arthritis characterized entation, disease course and treatment response, namely
by persistent joint inflammation lasting longer than systemic arthritis, oligoarthritis, polyarthritis (rheumatoid
6 weeks and beginning before the age of 16 years and has factor negative), polyarthritis (rheumatoid factor positive),
an unknown cause [1]. According to the classification psoriatic arthritis, enthesitis-related arthritis, and undiffer-
entiated arthritis [1]. Conventional pharmacological
therapies consist of non-biological, disease-modifying an-
* Correspondence:
†
Giovanna Ferrara and Greta Mastrangelo contributed equally to this work. tirheumatic drugs (DMARD), among which methotrexate
2
Rheumatology Unit, Anna Meyer Children Hospital and University of (MTX) is the most commonly prescribed [2].
Florence, University of Florence, Florence, Italy
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
, Ferrara et al. Pediatric Rheumatology (2018) 16:46 Page 2 of 14
To date, despite the wide use of MTX, there is a lack of topics were considered to represent clinically important
consensus-based clinical and therapeutic recommenda- issues facing clinicians caring for patients with JIA.
tions for the use of MTX in the management of patients
with JIA. Only two papers, one recently-published article Strategy for the literature search
from the Spanish Society of Paediatric Rheumatology A systematic search using PubMed and the Cochrane
(Sociedad Española de Reumatología Pediátrica; SERPE) Library for human studies published in English until the
[3], and an older article by the Pediatric Immunology and present was conducted on the 30th of November 2016.
Rheumatology Division of the Centre for Child Health, The keywords used in the search were “juvenile idiopathic
Heinrich-Heine-University, Düsseldorf, Germany [4] cur- arthritis” and “methotrexate” (“arthritis, juvenile”[MeSH
rently deal with this task. Terms] OR (“arthritis”[All Fields] AND “juvenile”[All
Thus, the aim of our group was to develop Fields]) OR “juvenile arthritis”[All Fields] OR (“juveni-
evidence-based recommendations for the use of MTX in le”[All Fields] AND “idiopathic”[All Fields] AND “arthriti-
the treatment of juvenile idiopathic arthritis. To this end, s”[All Fields]) OR “juvenile idiopathic arthritis”[All Fields])
the Methotrexate Advice and RecommendAtions on Ju- AND (“methotrexate”[MeSH Terms] OR “methotrexa-
venile Idiopathic Arthritis (MARAJIA) Expert Meeting was te”[All Fields]).
convened in Milan, Italy.
Study selection and data extraction
Methodology All papers found with the first search were initially se-
Development of the research topics lected as appropriate to the intended purpose on the basis
Establishing recommendations requires the use of formal of the title. Papers inconsistent with the main topic (for
methods, such as the nominal group technique (NGT), example for disease or drug) were excluded. A second
which is based on discussions by an Expert Panel to revision and selection was made reading the abstracts of
gather opinions and define a degree of consensus for remaining papers. Then all studies identified were read in
each statement. their full text.
A preliminary executive committee comprising Rolando
Cimaz, Giovanna Ferrara and Greta Mastrangelo was re- Critical appraisal of identified studies
sponsible for identifying key clinical issues using the PICO Each of the included studies was assessed for level of
(Population – Intervention – Comparator - Outcome) evidence using Oxford criteria for evidence-based levels of
system [5], with the aim of: 1) defining research questions, evidence [6]. The levels of evidence used in the analyses
and 2) developing criteria for selecting studies to be are summarized in Table 1. Evidence levels are indicative
reviewed by the Expert Panel in the development of clin- of quality regarding confidence and study design. In
ical and therapeutic recommendations for the manage-
ment of MTX in patients with JIA. The PICO framework Table 1 Levels of evidence [6]
is designed to help researchers to achieve relevant and
Levels of evidence
precise questions that can be answered in a systematic
1 Systematic review of all relevant
review structure, and allows improved specificity and randomized clinical trials or n-of-1 trials
conceptual clarity of the clinical question by splitting the
2 Randomized trial or observational
questions into smaller manageable components which are study with dramatic effect
more straightforward to identify in the literature search 3 Non-randomized controlled
process. cohort/follow-up study (observational)
The approach facilitates the identification of a precise 4 Case series, case-control study,
definition of a group of participants (Population), clear or historically controlled study
reporting of the drug exposures (Intervention) and the 5 Mechanism-based reasoning
control group interventions (Comparator) under consider- (expert opinion, based on physiology,
ation, and well-defined and clearly specified Outcomes of animal or laboratory studies)
the intervention being assessed. Finally, the type of Study Grades of recommendation
design to be included in the review should be reported. A Consistent level 1 studies
The executive committee identified nine clinically im- B Consistent level 2 or 3 studies,
portant research topics relating to the use of MTX in JIA or extrapolations from level 1 studies
using a structured PICO process. The topics covered effi- C Level 4 studies, or extrapolations
cacy and safety, dosages, routes of administration, tapering, from level 2 or 3 studies
and discontinuation of MTX, folic acid supplementation, D Level 5 evidence or troubling,
efficacy in JIA-associated uveitis, add-on therapy with inconsistent or inconclusive
studies of any level
biologic drugs, biomarkers, and vaccination. The selected
https://doi.org/10.1186/s12969-018-0255-8
REVIEW Open Access
Methotrexate in juvenile idiopathic arthritis:
advice and recommendations from the
MARAJIA expert consensus meeting
Giovanna Ferrara1†, Greta Mastrangelo2†, Patrizia Barone3, Francesco La Torre4, Silvana Martino5,
Giovanni Pappagallo6, Angelo Ravelli7, Andrea Taddio8, Francesco Zulian9, Rolando Cimaz2* On behalf of the
Rheumatology Italian Study Group
Abstract
Background: Conventional pharmacological therapies for the treatment of juvenile idiopathic arthritis (JIA) consist
of non-biological, disease-modifying antirheumatic drugs, among which methotrexate (MTX) is the most commonly
prescribed. However, there is a lack of consensus-based clinical and therapeutic recommendations for the use of
MTX in the management of patients with JIA. Therefore, the Methotrexate Advice and RecommendAtions on
Juvenile Idiopathic Arthritis (MARAJIA) Expert Meeting was convened to develop evidence-based recommendations
for the use of MTX in the treatment of JIA.
Methods: The preliminary executive committee identified a total of 9 key clinical issues according to the population,
intervention, comparator, outcome (PICO) approach, and performed an evidence-based, systematic, literature review.
During the subsequent Expert Meeting, the relevant evidence was assessed and graded, and 10 recommendations
were made.
Results: Recommendations relating to the efficacy, optimal dosing and route of administration and duration of
treatment with MTX in JIA, and to the issue of folic acid supplementation to prevent MTX side effects, use of MTX in
the treatment of chronic JIA-associated uveitis, combination treatment with biologic agents, and the use of vaccinations
in patients with JIA were developed. The selected topics were considered to represent clinically important issues facing
clinicians caring for patients with JIA. Evidence was insufficient to formulate recommendations for the use of biomarkers
predictive of treatment response.
Conclusions: These consensus recommendations provide balanced and evidence-based recommendations designed to
have broad value for physicians and healthcare clinicians involved in the clinical management of patients with JIA.
Keywords: Juvenile idiopathic arthritis, Methotrexate, Consensus
Background criteria of the International League of Associations for
Juvenile idiopathic arthritis (JIA) is one of the most Rheumatology (ILAR), the term JIA covers seven mutually
common chronic conditions of childhood. JIA comprises exclusive categories with differences in their clinical pres-
a group of heterogeneous forms of arthritis characterized entation, disease course and treatment response, namely
by persistent joint inflammation lasting longer than systemic arthritis, oligoarthritis, polyarthritis (rheumatoid
6 weeks and beginning before the age of 16 years and has factor negative), polyarthritis (rheumatoid factor positive),
an unknown cause [1]. According to the classification psoriatic arthritis, enthesitis-related arthritis, and undiffer-
entiated arthritis [1]. Conventional pharmacological
therapies consist of non-biological, disease-modifying an-
* Correspondence:
†
Giovanna Ferrara and Greta Mastrangelo contributed equally to this work. tirheumatic drugs (DMARD), among which methotrexate
2
Rheumatology Unit, Anna Meyer Children Hospital and University of (MTX) is the most commonly prescribed [2].
Florence, University of Florence, Florence, Italy
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
, Ferrara et al. Pediatric Rheumatology (2018) 16:46 Page 2 of 14
To date, despite the wide use of MTX, there is a lack of topics were considered to represent clinically important
consensus-based clinical and therapeutic recommenda- issues facing clinicians caring for patients with JIA.
tions for the use of MTX in the management of patients
with JIA. Only two papers, one recently-published article Strategy for the literature search
from the Spanish Society of Paediatric Rheumatology A systematic search using PubMed and the Cochrane
(Sociedad Española de Reumatología Pediátrica; SERPE) Library for human studies published in English until the
[3], and an older article by the Pediatric Immunology and present was conducted on the 30th of November 2016.
Rheumatology Division of the Centre for Child Health, The keywords used in the search were “juvenile idiopathic
Heinrich-Heine-University, Düsseldorf, Germany [4] cur- arthritis” and “methotrexate” (“arthritis, juvenile”[MeSH
rently deal with this task. Terms] OR (“arthritis”[All Fields] AND “juvenile”[All
Thus, the aim of our group was to develop Fields]) OR “juvenile arthritis”[All Fields] OR (“juveni-
evidence-based recommendations for the use of MTX in le”[All Fields] AND “idiopathic”[All Fields] AND “arthriti-
the treatment of juvenile idiopathic arthritis. To this end, s”[All Fields]) OR “juvenile idiopathic arthritis”[All Fields])
the Methotrexate Advice and RecommendAtions on Ju- AND (“methotrexate”[MeSH Terms] OR “methotrexa-
venile Idiopathic Arthritis (MARAJIA) Expert Meeting was te”[All Fields]).
convened in Milan, Italy.
Study selection and data extraction
Methodology All papers found with the first search were initially se-
Development of the research topics lected as appropriate to the intended purpose on the basis
Establishing recommendations requires the use of formal of the title. Papers inconsistent with the main topic (for
methods, such as the nominal group technique (NGT), example for disease or drug) were excluded. A second
which is based on discussions by an Expert Panel to revision and selection was made reading the abstracts of
gather opinions and define a degree of consensus for remaining papers. Then all studies identified were read in
each statement. their full text.
A preliminary executive committee comprising Rolando
Cimaz, Giovanna Ferrara and Greta Mastrangelo was re- Critical appraisal of identified studies
sponsible for identifying key clinical issues using the PICO Each of the included studies was assessed for level of
(Population – Intervention – Comparator - Outcome) evidence using Oxford criteria for evidence-based levels of
system [5], with the aim of: 1) defining research questions, evidence [6]. The levels of evidence used in the analyses
and 2) developing criteria for selecting studies to be are summarized in Table 1. Evidence levels are indicative
reviewed by the Expert Panel in the development of clin- of quality regarding confidence and study design. In
ical and therapeutic recommendations for the manage-
ment of MTX in patients with JIA. The PICO framework Table 1 Levels of evidence [6]
is designed to help researchers to achieve relevant and
Levels of evidence
precise questions that can be answered in a systematic
1 Systematic review of all relevant
review structure, and allows improved specificity and randomized clinical trials or n-of-1 trials
conceptual clarity of the clinical question by splitting the
2 Randomized trial or observational
questions into smaller manageable components which are study with dramatic effect
more straightforward to identify in the literature search 3 Non-randomized controlled
process. cohort/follow-up study (observational)
The approach facilitates the identification of a precise 4 Case series, case-control study,
definition of a group of participants (Population), clear or historically controlled study
reporting of the drug exposures (Intervention) and the 5 Mechanism-based reasoning
control group interventions (Comparator) under consider- (expert opinion, based on physiology,
ation, and well-defined and clearly specified Outcomes of animal or laboratory studies)
the intervention being assessed. Finally, the type of Study Grades of recommendation
design to be included in the review should be reported. A Consistent level 1 studies
The executive committee identified nine clinically im- B Consistent level 2 or 3 studies,
portant research topics relating to the use of MTX in JIA or extrapolations from level 1 studies
using a structured PICO process. The topics covered effi- C Level 4 studies, or extrapolations
cacy and safety, dosages, routes of administration, tapering, from level 2 or 3 studies
and discontinuation of MTX, folic acid supplementation, D Level 5 evidence or troubling,
efficacy in JIA-associated uveitis, add-on therapy with inconsistent or inconclusive
studies of any level
biologic drugs, biomarkers, and vaccination. The selected
